The investigator has shown that cytotoxic double deficiency (cdd) for perforin and Fas-L causes severe and lethal auto aggressive disease (cdd disease) in deficient mice. Moreover, cdd T-cells added to allogeneic bone marrow grafts permit bone marrow engraftment but are associated with severe and lethal graft-versus-host disease. Since the last submission, the investigators have been able to transfer cdd disease to syngeneic gld and wild type B6 recipients. Transferred cdd cells cause similar organ specific disease as in spontaneous disease. In addition, cdd T-cells cause defective thymic T-cell development. These data indicate that cdd T-cells are endowed with functional pathogenetic activity in spontaneous disease, upon transfer to syngeneic recipients and to allogeneic recipients. Cdd T-cells lack the two dominant cytolytic effectors, perforin and Fas-L. The ability of cdd T-cells to cause severe disease implies that effector molecules other than perforin and Fas-L are responsible for cdd T-cell pathogenicity. The application hypothesizes that these molecules are TNF, TRAIL and TWEAK and their respective receptors, TNF-R, Trail-Receptors, and DR3. The disease models already developed will be used to evaluate this hypothesis without interference by perforin and Fas-L. The specific aims are: 1) Delineate the role of the molecular effectors, TRAIL, TWEAK (DR3-L) and TNF in graft-versus-host disease mediated by perforin/Fas-L double deficient (cdd) T-cells following allogeneic bone marrow transplantation. 2) Define the molecular and cellular pathogenetic mechanisms of spontaneous cdd disease and syngeneic disease transfer. Since the last submission, the investigators have developed a disease transfer model for cdd disease showing a strong dominance of the cdd phenotype, and allowing analysis of the cellular and molecular pathogenesis of the disease. 3) Generate DR3 dominant negative transgenes expressed in T-cells to begin the analysis of DR3 function in lymphocyte homeostasis and cytotoxicity.